Zegerid

"The U.S. Food and Drug Administration today approved the first generic version of Nexium (esomeprazole magnesium delayed-release capsules) to treat gastroesophageal reflux disease (GERD) in adults and children ages 1 and older. Esomeprazole"...

Zegerid

CLINICAL PHARMACOLOGY

Mechanism Of Action

Omeprazole belongs to a class
of antisecretory compounds, the substituted benzimidazoles, that do not exhibit
anticholinergic or H2 histamine antagonistic properties, but that suppress
gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system
at the secretory surface of the gastric parietal cell. Because this enzyme
system is regarded as the acid (proton) pump within the gastric mucosa,
omeprazole has been characterized as a gastric acid-pump inhibitor, in that it
blocks the final step of acid production. This effect is dose related and leads
to inhibition of both basal and stimulated acid secretion irrespective of the
stimulus. Animal studies indicate that after rapid disappearance from plasma,
omeprazole can be found within the gastric mucosa for a day or more.

Results from a separate PK/PD
study of antisecretory effect on repeated once-daily dosing of 40 mg/1100 mg
and 20 mg/1100 mg of ZEGERID Capsules in healthy subjects show similar effects
in general on the above three PD parameters as those for ZEGERID 40 mg/1680 mg
and 20 mg/1680 mg Oral Suspension, respectively.

The antisecretory effect lasts
longer than would be expected from the very short (1 hour) plasma half-life,
apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme.

Enterochromaffin-like (ECL)
Cell Effects

In 24-month carcinogenicity
studies in rats, a dose-related significant increase in gastric carcinoid
tumors and ECL cell hyperplasia was observed in both male and female animals [See
Nonclinical Toxicology]. Carcinoid tumors have also been observed in
rats subjected to fundectomy or long-term treatment with other proton pump
inhibitors or high doses of H2-receptor antagonists. Human gastric biopsy
specimens have been obtained from more than 3000 patients treated with omeprazole
in long-term clinical trials. The incidence of ECL cell hyperplasia in these
studies increased with time; however, no case of ECL cell carcinoids,
dysplasia, or neoplasia has been found in these patients. These studies are of
insufficient duration and size to rule out the possible influence of
long-term administration of omeprazole on the development of any premalignant
or malignant conditions.

Serum Gastrin Effects

In studies involving more than 200 patients, serum
gastrin levels increased during the first 1 to 2 weeks of once-daily
administration of therapeutic doses of omeprazole in parallel with inhibition
of acid secretion. No further increase in serum gastrin occurred with continued
treatment. In comparison with histamine H2-receptor antagonists, the median
increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold
vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels,
usually within 1 to 2 weeks after discontinuation of therapy.

Other Effects

Systemic effects of omeprazole in the CNS, cardiovascular
and respiratory systems have not been found to date. Omeprazole, given in oral
doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function,
carbohydratemetabolism, or circulating levels of parathyroid hormone,
cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No
effect on gastric emptying of the solid and liquid components of a test meal
was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects,
a single I.V. dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor
secretion. No systematic dose-dependent effect has been observed on basal or
stimulated pepsin output in humans. However, when intragastric pH is maintained
at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased.

As do other agents that elevate intragastric pH,
omeprazole administered for 14 days in healthy subjects produced a significant
increase in the intragastric concentrations of viable bacteria. The pattern of
the bacterial species was unchanged from that commonly found in saliva. All
changes resolved within three days of stopping treatment.

The course of Barrett's esophagus in 106 patients was
evaluated in a U.S. double-blind controlled study of omeprazole 40 mg b.i.d.
for 12 months followed by 20 mg b.i.d. for 12 months or ranitidine 300 mg
b.i.d. for 24 months. No clinically significant impact on Barrett's mucosa by
antisecretory therapy was observed. Although neosquamous epithelium developed
during antisecretory therapy, complete elimination of Barrett's mucosa was not
achieved. No significant difference was observed between treatment groups in
development of dysplasia in Barrett's mucosa and no patient developed
esophagealcarcinoma during treatment. No significant differences between
treatment groups were observed in development of ECL cell hyperplasia, corpus
atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm
in diameter.

Pharmacokinetics

Absorption

In separate in vivo bioavailability studies, when ZEGERID
Oral Suspension and Capsules are administered on an empty stomach 1 hour prior
to a meal, the absorption of omeprazole is rapid, with mean peak plasma levels
(% CV) of omeprazole being 1954 ng/mL (33%) and 1526 ng/mL (49%), respectively,
and time to peak of approximately 30 minutes (range 10-90 min) after a
single-dose or repeated-dose administration. Absolute bioavailability of
ZEGERID Powder for Oral Suspension (compared to I.V. administration) is about
30-40% at doses of 20 – 40 mg, due in large part to presystemic metabolism.
When ZEGERID Oral Suspension 40 mg/1680 mg was administered in a two-dose
loading regimen, the omeprazole AUC (0-inf) (ng•hr/mL)
was 1665 after Dose 1 and 3356 after Dose 2, while Tmax was approximately 30
minutes for both Dose 1 and Dose 2.

Following single or repeated once daily dosing, peak
plasma concentrations of omeprazole from ZEGERID are approximately proportional
from 20 to 40 mg doses, but a greater than linear mean AUC (three-fold
increase) is observed when doubling the dose to 40 mg. The bioavailability of
omeprazole from ZEGERID increases upon repeated administration.

When ZEGERID is administered 1 hour after a meal, the
omeprazole AUC is reduced by approximately 24% relative to administration 1
hour prior to a meal.

Distribution

Omeprazole is bound to plasma proteins. Protein binding
is approximately 95%.

Metabolism

Following single-dose oral administration of omeprazole,
the majority of the dose (about 77%) is eliminated in urine as at least six
metabolites. Two metabolites have been identified as hydroxyomeprazole and the
corresponding carboxylic acid. The remainder of the dose was recoverable in
feces. This implies a significant biliary excretion of the metabolites of
omeprazole. Three metabolites have been identified in plasma – the sulfide and
sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites
have very little or no antisecretory activity.

Excretion

Following single-dose oral administration of omeprazole,
little if any, unchanged drug is excreted in urine. The mean plasma omeprazole
half-life in healthy subjects is approximately 1 hour (range 0.4 to 3.2 hours)
and the total body clearance is 500-600 mL/min.

Concomitant Use with Clopidogrel

In a crossover clinical study, 72 healthy subjects were
administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone
and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The
exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1)
and 42% (Day 5) when clopidogrel and omeprazole were administered together.
Results from another crossover study in healthy subjects showed a similar
pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg
daily maintenance dose) and omeprazole 80 mg daily when coadministered for 30
days. Exposure to the active metabolite of clopidogrel was reduced by 41% to
46% over this time period.

In another study, 72 healthy subjects were given the same
doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12
hours apart; the results were similar, indicating that administering
clopidogrel and omeprazole at different times does not prevent their
interaction.

Concomitant Use with Mycophenolate Mofetil

Administration of omeprazole 20 mg twice daily for 4 days
and a single 1000 mg dose of MMF approximately one hour after the last dose of
omeprazole to 12 healthy subjects in a cross-over study resulted in a 52%
reduction in the Cmax and 23% reduction in the AUC of MPA.

Special Populations

Geriatric

The elimination rate of omeprazole was somewhat decreased
in the elderly, and bioavailability was increased. Omeprazole was 76%
bioavailable when a single 40-mg oral dose of omeprazole (buffered solution)
was administered to healthy elderly subjects, versus 58% in young subjects
given the same dose. Nearly 70% of the dose was recovered in urine as
metabolites of omeprazole and no unchanged drug was detected. The plasma
clearance of omeprazole was 250 mL/min (about half that of young subjects) and
its plasma half-life averaged one hour, similar to that of young healthy
subjects.

Pediatric

The pharmacokinetics of ZEGERID has not been studied in
patients < 18 years of age.

Gender

There are no known differences in the absorption or
excretion of omeprazole between males and females.

Hepatic Insufficiency

In patients with chronic hepatic disease, the
bioavailability of omeprazole from a buffered solution increased to
approximately 100% compared to an I.V. dose, reflecting decreased first-pass
effect, and the mean plasma half-life of the drug increased to nearly 3 hours
compared to the mean half-life of 1 hour in normal subjects. Plasma clearance
averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects.
Dose reduction, particularly where maintenance of healing of erosive esophagitis
is indicated, for the hepatically impaired should be considered.

Renal Insufficiency

In patients with chronic renal impairment, whose
creatinine clearance ranged between 10 and 62 mL/min/1.73 m², the
disposition of omeprazole from a buffered solution was very similar to that in
healthy subjects, although there was a slight increase in bioavailability.
Because urinary excretion is a primary route of excretion of omeprazole
metabolites, their elimination slowed in proportion to the decreased creatinine
clearance. No dose reduction is necessary in patients with renal impairment

Asian Population

In pharmacokinetic studies of
single 20-mg omeprazole doses, an increase in AUC of approximately four-fold
was noted in Asian subjects compared to Caucasians. Dose adjustment,
particularly where maintenance of healing of erosive esophagitis is indicated,
for Asian subjects should be considered.

Animal Toxicology And/Or Pharmacology

Reproductive Toxicology Studies

Reproduction studies conducted
in pregnant rats with omeprazole at doses up to 138 mg/kg/day (about 33.6times
an oral human dose of 40 mg on a body surface area basis) and in pregnant
rabbits at doses up to 69 mg/kg/day (about 33.6times an oral human dose of 40
mg on a body surface area basis) did not disclose any evidence for a
teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of
6.9 to 69 mg/kg/day (about 3.3 to 33.6 times the human dose of 40 mg/day on a
body surface area basis) produced dose-related increases in embryo-lethality,
fetal resorptions and pregnancy disruptions. In rats, dose-related embryo/fetal
toxicity and postnatal developmental toxicity were observed in offspring
resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day
(about 3.3 to 33.6 times the human dose of 40 mg/day on a body surface area
basis).

Juvenile Animal Study

A 28-day
toxicity study with a 14-day recovery phase was conducted in juvenile rats with
esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 68 times a
daily oral human dose of 40 mg on a body surface area basis). An increase in
the number of deaths at the high dose of 280 mg /kg/day was observed when
juvenile rats were administered esomeprazole magnesium from postnatal day 7
through postnatal day 35. In addition, doses equal to or greater than 140
mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface
area basis), produced treatment-related decreases in body weight (approximately
14%) and body weight gain, decreases in femur weight and femur length, and affected
overall growth. Comparable findings described above have also been observed in
this study with another esomeprazole salt, esomeprazole strontium, at equimolar
doses of esomeprazole.

Clinical Studies

Duodenal Ulcer Disease

Active Duodenal Ulcer

In a multicenter, double-blind,
placebo controlled study of 147 patients with endoscopically documented
duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4
weeks was significantly higher with omeprazole 20 mg once a day than with
placebo (p ≤ 0.01). (See Table 6)

Table 6: Treatment of Active
Duodenal Ulcer % of Patients Healed

Omeprazole 20 mg a.m.
(n = 99)

Placebo a.m.
(n = 48)

Week 2

41*

13

Week 4

75*

27

* (p ≤ 0.01)

Complete daytime and nighttime
pain relief occurred significantly faster (p ≤ 0.01) in patients treated
with omeprazole 20 mg than in patients treated with placebo. At the end of the
study, significantly more patients who had received omeprazole had complete
relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).

In a multicenter, double-blind
study of 293 patients with endoscopically documented duodenal ulcer, the
percentage of patients healed (per protocol) at 4 weeks was significantly
higher with omeprazole 20 mg once a day than with ranitidine 150 mg b.i.d. (p
< 0.01). (See Table 7)

In a foreign multinational
randomized, double-blind study of 105 patients with endoscopically documented
duodenal ulcer, 40 mg and 20 mg of omeprazole were compared to 150 mg b.i.d. of
ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole were
statistically superior (per protocol) to ranitidine, but 40 mg was not superior
to 20 mg of omeprazole, and at 8 weeks there was no significant difference
between any of the active drugs. (See Table 8)

Table 8: Treatment of Active
Duodenal Ulcer % of Patients Healed

Omeprazole

Ranitidine 150 mg b.i.d.
(n = 35)

40 mg
(n = 36)

20 mg
(n = 34)

Week 2

83*

83*

53

Week 4

100*

97*

82

Week 8

100

100

94

*(p ≤ 0.01)

Gastric Ulcer

In a U.S. multicenter,
double-blind study of omeprazole 40 mg once a day, 20 mg once a day, and
placebo in 520 patients with endoscopically diagnosed gastric ulcer, the
following results were obtained. (See Table 9)

For the stratified groups of
patients with ulcer size less than or equal to 1 cm, no difference in healing
rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients
with ulcer size greater than 1 cm, 40 mg was significantly more effective than
20 mg at 8 weeks.

In a foreign, multinational,
double-blind study of 602 patients with endoscopically diagnosed gastric ulcer,
omeprazole 40 mg once a day, 20 mg once a day, and ranitidine 150 mg twice a
day were evaluated. (See Table 10)

Gastroesophageal Reflux Disease
(GERD)

Symptomatic GERD

A placebo controlled study was
conducted in Scandinavia to compare the efficacy of omeprazole 20 mg or 10 mg
once daily for up to 4 weeks in the treatment of heartburn and other symptoms
in GERD patients without erosive esophagitis. Results are shown in Table 11.

Erosive Esophagitis

In a U.S. multicenter
double-blind placebo controlled study of 40 mg or 20 mg of omeprazole delayed
release capsules in patients with symptoms of GERD and endoscopically diagnosed
erosive esophagitis of grade 2 or above, the percentage healing rates (per
protocol) were as shown in Table 12.

Table 12: % Patients Healed

Omeprazole 40 mg
(n = 87)

Omeprazole 20 mg
(n = 8 )

Placebo
(n = 43)

Week 4

45*

39*

7

Week 8

75*

74*

14

* (p < 0.01) Omeprazole
versus placebo.

In this study, the 40-mg dose
was not superior to the 20-mg dose of omeprazole in the percentage healing
rate. Other controlled clinical trials have also shown that omeprazole is
effective in severe GERD. In comparisons with histamine H2-receptor antagonists
in patients with erosive esophagitis, grade 2 or above, omeprazole in a dose of
20 mg was significantly more effective than the active controls. Complete
daytime and nighttime heartburn relief occurred significantly faster (p <
0.01) in patients treated with omeprazole than in those taking placebo or
histamine H2-receptor antagonists.

Long Term Maintenance Treatment
Of Erosive Esophagitis

In a U.S. double-blind,
randomized, multicenter, placebo controlled study; two dose regimens of
omeprazole were studied in patients with endoscopically confirmed healed
esophagitis. Results to determine maintenance of healing of erosive esophagitis
are shown in Table 13.

A double-blind, multicenter,
randomized, non-inferiority clinical trial was conducted to compare ZEGERID
Oral Suspension 40 mg/1680 mg and I.V. cimetidine for the reduction of risk of
upper gastrointestinal (GI) bleeding in critically ill patients (mean APACHE II
score = 23.7). The primary endpoint was significant upper GI bleeding defined
as bright red blood which did not clear after adjustment of the nasogastric
tube and a 5 to 10 minute lavage, or persistent Gastroccult® positive coffee
grounds for 8 consecutive hours which did not clear with 100 cc lavage. ZEGERID
Oral Suspension 40 mg/1680 mg (two doses administered 6 to 8 hours apart on the
first day via orogastric or nasogastric tube, followed by 40 mg q.d.
thereafter) was compared to continuous I.V. cimetidine (300 mg bolus, and 50 to
100 mg/hr continuously thereafter) for up to 14 days (mean = 6.8 days). A total
of 359 patients were studied, age range 16 to 91 (mean = 56 yrs), 58.5% were
males, and 64% were Caucasians. The results of the study showed that ZEGERID
was non-inferior to I.V. cimetidine, 10/181(5.5%) patients in the cimetidine
group vs. 7/178 (3.9%) patients in the ZEGERID group experienced clinically
significant upper GI bleeding.